The present invention relates to emulsions comprising highly fluorinated or perfluorinated compounds. More particularly, it relates to fluorocarbon emulsions exhibiting reduced pulmonary gas-trapping properties.
Fluorocarbon emulsions find uses as therapeutic and diagnostic agents. Most therapeutic uses of fluorocarbons are related to the remarkable oxygen-carrying capacity of these compounds. One commercial biomedical fluorocarbon emulsion, Fluosol (Green Cross Corp., Osaka, Japan), is presently used as an oxygen carrier to enhance oxygen delivery to the myocardium during percutaneous transluminal coronary angioplasty (Fluosol, Summary Basis of Approval, Reference No. OB-NDA86-0909, December 1989). Fluorocarbon emulsions have also been used in diagnostic applications such as imaging. Radiopaque fluorocarbons such as perflubron (perfluorooctyl bromide or C.sub.8 F.sub.17 Br) are particularly useful for this purpose.
Increased pulmonary residual volume (IPRV) has been observed in association with the intravenous administration of various perfluorocarbon emulsions in certain animal species. While the direct correlation between IPRV and pulmonary dysfunction has not been positively identified, dysfunction (including reduced arterial PO.sub.2, signs of respiratory distress, and even lethality) has been observed on occasions in certain sensitive animal species in which IPRV was later identified.
IPRV occurs as a result of gas-trapping within the pulmonary system, and prevents the normal deflation of lungs when intrathoracic pressure is equalized to ambient pressure such as during necropsy of an animal. It is believed that gas-trapping occurs as a consequence of foam or bubble formation in the lungs. It is noted that under normal circumstances, bubbles or liquid bridges form and disappear spontaneously within alveoli without a gas-trapping effect. It is believed, however, that IPRV occurs when these bubbles grow in the presence of fluorocarbon vapors, trapping larger amounts of air within the lung. As stated above, if bubble formation continues, pulmonary dysfunction can result (in certain animal species). IPRV depends on the vapor pressure of the fluorocarbon component(s), with lower vapor pressure fluorocarbons not exhibiting the phenomenon. Diminution of the vapor pressure of the fluorocarbon component(s) also plays a critical role in stabilizing the emulsion droplets against Ostwald ripening, the key destabilizing mechanism at work in small particle fluorocarbon emulsions. The prior art has described fluorocarbon emulsion formulations designed to inhibit Ostwald ripening. See, e.g. Davis et al., U.S. Pat. No. 4,859,363; Meinert, U.S. Pat. No. 5,120,731; Kabalnov et al., Kolloidn Zh., 48: 27-32 (1986). These formulations contain a mixture of two fluorocarbon components, the secondary fluorocarbon component having a significantly higher molecular weight, and lower vapor pressure relative to the primary fluorocarbon component.
Following intravenous administration, fluorocarbon emulsion particles are taken up and temporarily retained by cells of the reticuloendothelial system (RES). It is desirable to minimize this retention time (all references to organ half-life or organ retention which follow refer specifically to retention in the RES organs, principally liver and spleen). Unfortunately, when the prior art included higher molecular weight fluorocarbons in fluorocarbon emulsions, organ retention times were also increased considerably. Organ retention times for most fluorocarbons bear an exponential relationship to the molecular weight of the fluorocarbon and are critically dependent on dose and animal species. See J. G. Riess, Artificial Organs 8: 44, 49-51 (1984); J. G. Riess, International Symposium on Blood Substitutes, Bari, Italy: Jun. 19-20, 1987, Proceedings pp. 135-166.
There is a need for perfluorocarbon emulsions that do not exhibit, or exhibit reduced pulmonary gas-trapping properties, and also have a short organ retention time. Accordingly, it is an object of the invention to provide fluorocarbon emulsions having these characteristics.